Method and apparatus for enhanced size reduction of particles

ABSTRACT

The present invention provides methods and apparatus for producing particles via supercritical fluid processing. In one embodiment, the method includes expanding a supercritical fluid plasticized melt across a pressure drop to form solid composite particles that are simultaneously dispersed, foamed and cooled, and milling the solid particles produced to achieve the desired size distribution. In another embodiment, a pressure vessel containing a supercritical fluid plasticized melt is depressurized to form a cooled solid porous mass, which is then milled to obtain solid composte particles.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates generally to methods and apparatus forproducing particles, and particles formed thereby.

2. Description of Related Art

The enhanced mass-transfer properties and benign nature of supercriticalfluid, near-critical fluid and/or compressed gas (hereinaftercollectively referred to as “supercritical fluid”), makes it particularsuitable for use in the production of particles. One prior arttechnique, which is often referred to in the art as Particles fromGas-Saturated Solutions (PGSS), employs supercritical fluid for thispurpose.

In the conventional PGSS process, supercritical fluid is used toplasticize a material thereby forming a melt. The melt thus formed isthen expanded across a pressure drop. As the melt expands, thesupercritical fluid changes phase and diffuses out of the melt as a gas,which leads to the formation of particles. A conventional PGSS processis described in U.S. Pat. No. 5,766,636, which is hereby incorporated byreference in its entirety. Advantages of the PGSS process include lowprocessing temperatures for thermally labile compounds, relatively easyscalability and one step processing of particles.

A significant disadvantage of the conventional PGSS process is that itoften is not sufficient to lower the viscosity of the melt. This isespecially problematic with the processing of many high molecular weightpolymers. Because the viscosity of the melt is not sufficiently low andthe concentration of the supercritical fluid in the melt is notsufficiently high at feasible operating conditions (i.e., a temperaturebelow about 373 Kelvin (K) and a pressure below about 30 megaPascal(MPa)), efficient particle dispersion and size reduction is difficult.

A particle production technique having benefits of conventional PGSSprocessing but having improved processability is desirable.

BRIEF SUMMARY OF THE INVENTION

The present invention provides methods and apparatus for producingcomposite particles using supercritical fluid. In accordance with afirst method of the invention, a load stock comprising an excipient anda biologically active substance is contacted with a supercritical fluidto form a melt. The melt is expanded across a pressure drop, whichcauses at least a portion of the supercritical fluid to diffuse out ofthe melt. The diffusion of supercritical fluid out of the melt causesthe melt to break into smaller particles and solidify practicallysimultaneously. The expansion of the supercritical fluid is the forcefor this particle micronization and also produces a porous networkwithin the solid particles (i.e., foaming). In some cases, a rapidtemperature decrease can also contribute to a thermal fracture of thesolidified particles into smaller particles. For example, the expansionof a melt plasticized with supercritical carbon dioxide (CO₂) will chillthe resulting particles to a temperature below 0° C. due to theJoule-Thomson effect. In some cases, depending upon the temperature andamount of CO₂ present, dry ice (solid CO₂) can be formed. Further, theaverage particle size of the solid particles is reduced using a suitablemilling device, preferably before the temperature of the solid particlesis permitted to return to ambient temperature. More preferably, themilling step is performed before the temperature of the solid particlesis permitted to rise to or above 0° C. Dry ice can be used as an aid incooling and micronizing the solid particles.

In a second alternative embodiment of the invention, supercritical fluidis used to plasticize a load stock in a vessel. Instead of passing themelt across a pressure drop, the vessel is rapidly depressurized.Depressurization of the vessel causes the supercritical fluid to diffusefrom the melt resulting in the formation of a solid, porous mass.Depressurization of the vessel also results in a rapid temperaturereduction. For example, the expansion of supercritical CO₂ from aplasticized load stock can result in the formation of a porous, solidmass and dry ice. The porous, solid mass and the dry ice can then bemilled using a suitable milling device before the temperature of thesolid mass is permitted to return to ambient temperature. The millingdevice, such as grinding rotors, rollers or balls, can be incorporatedinto the vessel so that the micronization process can occur immediatelyafter the expansion. The alternative embodiment of the invention isparticularly suitable for forming solid particles from materials thathave too high of a viscosity when plasticized to be efficientlydispersed through an expansion nozzle.

The foregoing and other features of the invention are hereinafter morefully described and particularly pointed out in the claims, thefollowing description setting forth in detail certain illustrativeembodiments of the invention, these being indicative, however, of but afew of the various ways in which the principles of the present inventionmay be employed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of an apparatus for use in carryingout the method of the invention.

FIG. 2 is a block diagram of the steps of a method according to theinvention.

FIG. 3 is a scanning electron micrograph of the particles produced inExample 1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method and an apparatus for producingsolid particles. In accordance with the method of the invention, a loadstock comprising an excipient and a biologically active substance isplasticized using supercritical fluid to form a melt. The term “melt” asused in this context denotes that the supercritical fluid diffuses intothe load stock and thereby reduces its viscosity (e.g., viaplasticization, swelling or dissolution) so as to render it fluid orsemi-fluid, which can be further processed as such. In some embodimentsof the invention, the melt can be flowed, pumped or sprayed as a fluidor semi-fluid. The supercritical fluid dissolves into the load stockcausing it to liquefy or plasticize into a melt at temperaturespreferably lower than the melting point or glass transition temperatureof the components of the load stock.

In a first embodiment of the invention, the supercriticalfluid-saturated melt is expanded across a pressure drop, typicallythrough a nozzle. Expansion of the melt across the pressure drop causesthe supercritical fluid to undergo a phase change (from a supercriticalfluid phase to a gaseous phase), thereby causing the gas to escape andthe melt to solidify into solid particles, often having a porousstructure. The expansion of the supercritical fluid reduces thetemperature of the solid particles. In some cases, the temperature ofthe particles is reduced to below 0° C., and more preferably,substantially below 0° C.

The solid particles are transferred, either directly or indirectly, intoa milling device. The milling device may or may not be a part of thesame vessel where the expansion of the supercritical fluid takes place.The milling devices mills or comminutes the solid particles into finerparticles of near uniform shape and size. Milling is preferablyaccomplished before the temperature of the solid particles is permittedto rise to ambient temperature. More preferably, milling is performedbefore the temperature of the solid particles is permitted to rise to orabove 0° C. Most preferably, the solid particles formed during theexpansion step are directly transferred to the milling device at the lowtemperature produced during expansion.

Because the temperature of the solid particles is low, and because thesolid particles tend to be porous, the solid particles can beefficiently milled or comminuted into smaller particles of near uniformshape and size. In some instances, it is advantageous for a portion ofthe supercritical fluid to freeze into a solid form, which can be usedas a milling media during the solid particle reduction step. Dry ice,for example, can be formed upon the expansion of supercritical CO₂,which can be used to keep the temperature of the solid particles verylow and also as a milling media.

The excipient present in the solid particles protects the biologicallyactive substance from local heating and shearing during milling, thusfacilitating the micronization of the biologically active substance.

In a second embodiment of the invention, which is suitable for use withhighly viscous melts that are difficult to pump through a nozzle acrossa pressure drop, a solid porous and brittle mass can be formed bycontacting a load stock with supercritical fluid in a pressure vessel toform a plasticized melt. The vessel can then be depressurized at a rapidrate. The depressurization of the vessel decreases the temperaturewithin the vessel. Depressurization of the vessel allows thesupercritical fluid to undergo a phase change, which results in theformation of a solid porous mass (e.g., foam), which may be a singlechunk or several fractured chunks. The low temperature, which ispreferably below 0° C., makes the solid porous mass brittle. The solidporous mass is then transferred to a milling device, preferably at thesame low temperature as obtained during expansion, and milled to formparticles that have a near uniform size and shape. In this case, themilling device can be a part of the same expansion vessel so thatmaterials can be milled immediately after expansion.

A schematic system or apparatus 100 for implementing the methodaccording to the invention is shown in FIG. 1. The apparatus 100includes a mixing assembly 102, an expansion assembly 104, and a millingassembly 106. The mixing assembly 102 includes a mixing vessel 110, asolvent pump 112, a supercritical fluid pump 114, and a mixer 116.

The mixing vessel 110 is preferably tubular and defines an axis 120, andhas first and second ends 122, 124 that are spaced axially apart.Preferably, the axis 120 is oriented vertically such that the first end122 is below the second end 124. That is, the second end 124 is UP andthe first end 122 is DOWN when moving along the axis 120. The mixingvessel 110 has an inner surface that defines a mixing chamber 130. Thepressure in the mixing chamber 130 is denoted with the reference numberP1. The mixing assembly 102 has means, not shown, for accessing theinterior of the mixing vessel 110 so as to charge the interior with aload stock.

As previously noted, the load stock comprises an excipient and abiologically active substance. Throughout the instant specification andin the appended claims, the term “excipient” refers to any one or acombination of generally inert, natural or synthetic substances that areused in the pharmaceutical industry as binders and/or carrier materialsfor biologically active substances. Suitable excipients for use in theinvention include, for example, polymers, waxes, lipids and combinationsthereof. The excipient or excipients used in the invention arepreferably solids at 25° C. and 1 atmosphere pressure. Suitable polymersfor use in the invention include, for example, polysaccharides,polyesters, polyethers, polyanhydrides, polyglycolides (PLGA),polylactic acid (PLA), polycaprolactone (PCL), polyethylene glycol (PEG)and polypeptides. Suitable lipids include, for example, glycerides.Examples of “biologically active substances” include, for example,drugs, peptides, proteins, pharmaceuticals, biopharmaceuticals andtherapeutic agents.

In the preferred embodiment of the invention, the biologically activesubstance is incorporated with the excipient in a desired manner to forma coated, encapsulated or taste-masked formulation, or a controlledprolonged or sustained release formulation. It will be appreciated thatthe load stock can also further comprise other substances such as, forexample, pigments, sugars, diagnostic aids and/or markers, nutritionalmaterials, proteins, peptides, animal and/or plant extracts, dyes,antigens, catalysts, nucleic acids and combinations thereof.

The load stock must be capable of forming a melt when contacted with asupercritical fluid under pressure. Throughout the instant specificationand in the appended claims, the term “melt” denotes that thesupercritical fluid reduces the viscosity of the load stock (e.g., viaplasticization, swelling or dissolution) so as to render it a fluid orsemi-fluid that can be processed as such. In other words, the load stockcan be flowed, pumped or sprayed as a fluid or semi-fluid.

The supercritical fluid pump 114 is preferably a P-200 high-pressurereciprocating pump commercially available from Thar Technologies, Inc.(Pittsburgh, Pa.). Suitable alternative pumps include diaphragm pumpsand air-actuated pumps that provide a continuous flow of supercriticalfluid. The high-pressure pump 114 preferably comes factory-equipped witha burst-type rupture disc, manufactured by Fike Inc. (Blue Springs,Mo.), which is plumbed into a pressure relief system.

The supercritical fluid pump 114 pumps supercritical fluid through asurge tank 140 and a metering valve 142 so as produce a pulse-free flow.Because the supercritical fluid pump 114 is in fluid communication withthe mixing chamber 130, the supercritical fluid pump 114 can supplysupercritical fluid through the surge tank 140 into the chamber 130.

With reference to the supercritical fluid that the supercritical fluidpump 114 supplies to the chamber 130, as noted hereinabove and usedherein “supercritical fluid” includes not only supercritical fluid, butalso compressed gas and liquefied gas, and other materials suitable, forexample, to form a melt as described herein. The supercritical fluid ispreferably supercritical carbon dioxide (“CO₂”). Suitable alternativefluids include, nitrous oxide, dimethylether, straight chain or branchedC1-C6-alkanes, alkenes, ethane, propane, fluoroform,chlorotrifluoromethane, chlorodiflueromethane, propylene, ammonia andcombinations thereof. Preferred alkanes include ethane, propane, butane,isopropane, and the like.

The supercritical fluid is chosen generally with reference to theability of the supercritical fluid to melt, swell or plasticize the loadstock during a mixing and melt formation operation. The freezing orsolidification point of the supercritical fluid is also a factor inselecting the supercritical fluid for use in a method according to thepresent invention.

The mixer apparatus 116 includes a motor 150, a shaft 152 extending fromthe motor 150 through the second end 124 of the mixing vessel 110 andinto the chamber 130, and a rotor 154 disposed at a distal end of theshaft 152 and located in the chamber 130. The mixing rate is controlledby the rotation speed and geometry (type and diameter) of the rotor 154.The rotor 154 is preferably a propeller-shaped two-bladed mixer.Additional, supplemental and alternative mixing methods include bothstatic and moving mixing devices, such as baffles, rotors, turbines,shear-mixers, ultrasonic devices, and other devices or mechanisms usedto mix the contents of the mixing assembly 102.

With reference to the expansion assembly 104, the expansion assembly 104communicates with the mixing assembly 102 via a release valve 168. Therelease valve 168 is preferably a model R3A ¼″ proportional pressurerelease valve, which is commercially available from Swagelok, Inc.(Solon, Ohio). The release valve 168 is actuated by system pressureacting against a spring, and is capable of reseating. Additional releasevalves (not shown) are located in regions of the system 100 which areisolatable between two other valves, and are piped into a dedicatedrelief venting system. The release valve 168 is thus disposed betweenthe mixing vessel 110 and the expansion vessel 160, and is in fluidcommunication with a nozzle 164.

In order to pass the melt across a pressure drop as described in thefirst method of the invention, the expansion assembly 104 preferablyincludes a receiving or expansion vessel 160, which is preferablytubular, a backpressure regulator 162 and a nozzle 164. The expansionvessel 160 has an inner surface that defines an expansion chamber 170.The pressure inside the expansion chamber is denoted with referencenumber P2. The expansion vessel 160 has an outlet 196 that opensdirectly into the milling assembly 106. The solid particles can betransferred into the milling assembly 106 directly from the expansionchamber while still under the influence of the temperature reduction.The supercritical fluid can behave as both a transporting medium both bymaintaining particle flow through the milling device, and as a heat sinkor temperature modifier.

Preferably, the supercritical fluid-saturated melt is expanded directlyinto the milling device. Where an expansion vessel that is separatedfrom the milling device is used, the melt is expanded into the expansionchamber and then communicated to the milling device while still at thereduced temperature. The solid particles can be transferred into themilling assembly 106 directly from the expansion chamber while stillunder the influence of the temperature reduction. The supercriticalfluid can behave as both a transporting medium both by maintainingparticle flow through the milling device, and as a heat sink ortemperature modifier.

The backpressure regulator 162 is preferably a model 26-1700 regulator,which is commercially available from Tescom, USA (Elk River, Minn.). Thebackpressure regulator 162 maintains the pressure P2 in the expansionchamber 170 in a predetermined range of pressures during operation ofthe apparatus 100.

The milling assembly 106 communicates with the expansion assembly 104via the outlet 174 from the expansion assembly 104. The milling assembly106 includes a milling vessel 180, a milling device 182, a filter 184,and optionally a second backpressure regulator 186. The milling vessel180 has an inner surface that defines a mill chamber 188. The millingdevice 182 is disposed within the mill chamber 188 and communicates withthe outlet 174. Accordingly, material from the expansion chamber 170 canflow into the milling device 182 through the outlet 174, and preferablydirectly into the milling device 182.

The milling device 182 is preferably is a jet mill or a COMIL modelcryogenic mill, which is commercially available from Quadro, Inc.(Milburn, N.J.). Other suitable size reducing devices or mills include ahigh-energy bead mill or attritor mill, rod mill, roller mill, ceramicball mill, media mill, fluidized energy mill, cryogenic comminuter,ultrasonic comminuter, grinder, and the like.

The filter 184 is disposed adjacent to the second backpressure regulator186. The filter 184 can block solid material from flowing into thesecond backpressure regulator 186. A thermostat 190 communicates withheating elements (not shown) that are located proximate to the mixingvessel 110, the expansion vessel 160, the milling vessel 180, and therelease valve 168. A controller 192 communicates with and controls thesolvent pump 112, the supercritical fluid pump 114, the thermostat 190,the mixer apparatus 116, the backpressure regulators 162, 186, themilling device 182, and the release valve 168. Standard controllers arecommercially available, and are interchangeable therewith.

Thus, the first embodiment of the method of the invention involvescharging the mixing vessel 102 with a load stock comprising an excipientthat is a solid at 25° C. and 1 atmosphere pressure and a biologicallyactive substance (see FIG. 2, step 200). The controller 192 activatesthe supercritical fluid pump 114 to supply a quantity of supercriticalfluid through the surge tank 140, through the metering valve 142, andinto the mixing chamber 130 (step 202). The addition of supercriticalfluid increases the pressure P1 in the mixing chamber 130. Thethermostat 190 and the supercritical fluid pump 114 cooperate tomaintain the temperature and the pressure P1, respectively, in agenerally constant operating range. Accordingly, the pressure P1 isgenerally in a range that is increased relative to atmospheric pressure.Preferably, the supercritical fluid is maintained in the predeterminedrange such that the supercritical fluid remains in a supercriticalstate.

The supercritical fluid contacts the load stock in the mixing chamber130. The controller 192 controls the mixer apparatus 116 to engage themotor 150 so as to rotate the shaft 152. The rotor 154 mixes thesupercritical fluid and the load stock together until a uniform mixtureis achieved. The load stock forms a melt 190 when mixed with thesupercritical fluid under pressure (step 204).

In some cases, it is desirable for the load stock to further comprise asolvent. Solvents can interact with and affect the visco-elasticproperties of the load stock and/or the molten mass to enhance mixingand blending in the mixing vessel 110. The solvent can be added to themixing chamber 130 prior to the introduction of supercritical fluid or,alternatively, can be added using the solvent pump 112 after or duringintroduction of the supercritical fluid. If desired, excesssupercritical fluid can be circulated through the mixing chamber 130prior to expansion to extract supercritical fluid soluble solvents fromthe melt, to the extent any are present. Preferably, the solvent isremoved before expansion of the melt. The solvent or solvent(s) used inthe invention can be organic solvents or inorganic solvents. Examples ofsuitable solvents include acetone, water, methanol, ethanol, toluene,ethyl acetate, methylene chloride, dimethyl sulfoxide and dimethylformamide.

The melt 194 is then expanded across a pressure drop (step 206),typically through a nozzle 164, into a collection chamber 160. Tofacilitate and control the expansion of the melt, the controller 192controls the backpressure regulator 162 and the release valve 168 toinfluence the pressure P2 in the expansion chamber 170. Thus, thepressure P2 is preferably increased relative to atmospheric pressure,but decreased relative to the pressure P1 in the mixing chamber 130.Because the pressure P1 in the mixing chamber 130 is greater thanatmospheric pressure, increasing the pressure P2 in the expansionchamber 170 reduces the size of the pressure differential between thepressures P1, P2 in the chambers 130, 170. By affecting the pressuredifferential, the size and morphology of the resultant solid particlescan be controlled. Generally, the larger the pressure differential thesmaller the resultant solid particles that are produced.

The controller 192 controls the release valve 168 to switch from aclosed condition to an open condition. In response to the opening of therelease valve 168, and under the influence of the pressure differentialbetween the chambers 130, 170, the melt 194 flows through the releasevalve 168 and further though the nozzle 164. The pressurized melt 194 issprayed from the nozzle 164 either into the chamber or directly into themilling device 170. Because of the pressure reduction of the melt 194during expansion (from the pressure P1 in the mixing chamber 130 to therelatively lower pressure P2 in the expansion chamber), thesupercritical fluid contained in the melt 194 diffuses out of the meltand thereby increases the melt point and/or glass transition temperatureof the melt 194, decreases the temperature of the melt 194, and expandsto increase the volume of the melt 194.

In response to the expansion, the melt 194 solidifies into solidparticles 196 comprising the load stock (step 206). The phase change ofthe supercritical fluid from liquid to gas reduces the localizedtemperature of materials adjacent to the expansion location (i.e., atthe nozzle outlet). Further, a portion of the supercritical fluid maycrystallize or freeze in response to the temperature reduction, asdiscussed hereinabove. Whether a portion of the supercritical fluidcrystallizes is determined by factors such as the selection ofsupercritical fluid, and the temperature and pressure of the expansionchamber during operation. The solid particles will have a temperaturebelow 0° C.

In addition, any other materials that were added to the melt 194, forexample, during the mixing and formation of the melt 194 (reference step204), are also formed or are co-precipitated into the solid particles196. For example, if any materials are dissolved, and/or suspended inthe supercritical fluid, the dissolved or suspended materialsprecipitate or solidify during the expansion and phase change of thesupercritical fluid. The solid particles 196 can thus form compositesolid particles that collect in the expansion chamber 170. Accordingly,the solid particles can be microspheres or microcapsules, and the like.Rather than discrete solid particles, the expanded material can beprecipitated as a suspension, a foam, a web, or a gel, and the solidparticles can have different surface profiles or morphologies or can begrouped or agglomerated. The solid particles 196 form a suspension inthe solvent if the solvent is not removed during the mixing or theexpansion step.

In the first embodiment of the invention, the solid particles 196 areimmediately directed into the milling device 182 (step 208).Alternatively, the solid particles 196 are milled in a separate millingdevice. In addition, the milling device can be incorporated into themixing chamber 130, so that the entire batch can be milled withouttransferring the solid material into a separate milling apparatus. Themilling device 182 grinds, comminutes or micronizes the solid particles196 to reduce their average particle size before the temperature of thesolid particles is permitted to rise above 0° C. It will be appreciatedthat grinding may cause the temperature of the solid particles toincrease above 0° C., but the temperature of the solid particles must bebelow 0° C. when the grinding operation commences. Preferably, frozenfluid particles are present during grinding, and are co-micronized bythe milling device 182. The fluid particles act as grinding media tofurther enhance the size reduction or morphology of the solid particles196.

In the second embodiment of the invention for cases where the meltviscosity is high, the melt is first converted into a low temperaturesolidified porous mass by rapid depressurization of the mixing vessel.The mass thus obtained is collected from the mixing vessel thencommunicated into a separate milling device to form fine uniform sizedparticles. The mixing vessel used here is similar to the one descried inthe earlier embodiment.

Preferably, micronized solid particles 198 having a narrow sizedistribution and a mean size in a range of from about 0.1 μm to about500 μm are collected in the milling chamber 188. By varying the processconditions, it is possible to obtain particles having a desired meansize within a desired particle size distribution for particularpharmaceutical applications and/or drug delivery routes. The micronizedsolid particles 198 are then brought to ambient temperatures andpressures. As a result of the change in the temperature and/or pressure,frozen fluid particles, if present, sublime and are removed or separatedfrom the micronized solid particles 198. If solvent, surfactant or otherundesirable processing aid is present in the micronized solid particles198, the micronized solid particles 198 can be filtered and/or washed toremove the solvent, surfactant and/or aid.

Accordingly, the advantages of expanding the melt with a supercriticalfluid, and of milling a mixture of solid particles and solid and frozenfluid particles, are obtained with a reduced reliance on the particlemicronization during expansion through the nozzle, the diffusion ratesof supercritical fluid from the melt and the shear stresses experiencedduring flow through the nozzle. Solidified fluid particles present,helps maintain a reduced temperature during milling following theexpansion stage. The porous structure of such particles greatly enhancesthe milling process. Further more, the excipient present in thecomposite solid particles helps protect the biologically activesubstance from local heating and shear stresses during milling. Thesefactors help preserve the stability of thermally labile and shear-labilebiologically active substances such as, for example, peptides andproteins.

The following examples are intended only to illustrate the invention andshould not be construed as imposing limitations upon the claims. Unlessspecified otherwise, all ingredients are commercially available fromsuch common chemical suppliers as Sigma Aldrich, Inc. (St. Louis, Mo.)and/or Fisher Scientific International, Inc. (Hanover Park, Ill.).

EXAMPLE 1

Preparation.

Initially, 5 grams (g) of EUDRAGET RS100 and 1.6 g acetaminophen(paracetamol) were dissolved into 15 milliliters (ml) of acetone. Thesolution was charged to a mixing vessel. The mixing vessel defined achamber having a volume of 100 ml and had a diameter of 32 millimeters(mm). The chamber was pressurized with carbon dioxide gas (CO₂) to anoperating pressure of 30 megaPascal (MPa), and heated to a temperatureof 323 Kelvin (K).

At the predetermined temperature and pressure, the carbon dioxide becamesupercritical. The controller was set to maintain the mixer to rotatethe mixer blade at a constant agitation speed of 4000 revolutions perminute (rpm). The ingredients were mixed for 30 minutes.

Carbon dioxide was circulated through the mixing vessel during themixing stage. The circulating carbon dioxide removed the acetone fromthe solution, thus forming a residual homogeneous mass or melt ofacetaminophen crystals and EUDRAGIT carrier.

Expansion of Particles.

A release valve was opened to communicate the contents of the mixingvessel, i.e. the melt, to an expansion vessel. Specifically, the releasevalve communicated the mixture to a nozzle that opened into the interiorof the expansion vessel with an excess of carbon dioxide. The nozzle hadan orifice with a diameter of 1.19 millimeter (mm). The pressure in theinterior of the expansion vessel was above standard atmosphericpressure, but below 30 MPa. The pressure in the mixing vessel wasadjusted to remain at a constant 30 MPa. The expansion caused both apressure reduction and a temperature reduction. As a result of thepressure reduction, a portion of the carbon dioxide phase changed to agas and supersaturated the melt. In response to the supersaturation, themelt formed or precipitated into solid particles. As a result of thetemperature reduction, another portion of the carbon dioxide formed intofrozen supercritical fluid particles. The frozen supercritical fluidparticles and solid particles were intimately mixed during therespective formations.

The solid particles and frozen supercritical fluid particles werecollected and directed into a mill. The mill was a rotary grinderoperating at a speed of 10,000 revolutions per minute (RPM). The solidparticles and the frozen supercritical fluid particles were groundtogether and collected into the mill vessel bottom.

Analysis of the Particles.

Analysis of the particles was performed using a Scanning ElectronMicroscope (SEM) to determine size and morphology, using an X-ray powderdiffraction spectrometer (XPD) to determine solid phase/crystallinity,and using a laser diffraction particle analyzer to determine particlesize distribution.

The particles produced had a mean particle diameter of 18.4 micrometers(μm). X-ray phase analysis determined that more than 90% of theacetaminophen was contained in the crystalline form coated by amorphousEUDRAGET polymer.

EXAMPLE 2

Preparation.

Initially, 10 grams (g) of Polyester was loaded into the mixing vesseldescribed in Example 1. The vessel was pressurized with carbon dioxidegas (CO₂) to an operating pressure of 30 megaPascal (MPa), and heated toa temperature of 333 (K). The controller was set to maintain the mixerto rotate the mixer blade at a constant agitation speed of 2000revolutions per minute (rpm). The polymer was mixed for 30 minutes.

Expansion.

A release valve was opened at the top of the mixing vessel to reduce thepressure of the mixture from 30 MPa to 1 bar for about 10 s. Theexpansion caused both a pressure reduction and a temperature reduction.The melt formed a porous mass of polymer and dry ice.

The resulting porous solid was collected and directed into a rotarygrinder operating at a speed of 10,000 revolutions per minute (RPM). Forcomparison, solid untreated polymer in the form of flakes (between 1-2mm size) was mixed with dry ice and subjected to the same micronizationprocedure.

Analysis of the Particles.

Analysis of the particles was performed using a Scanning ElectronMicroscope (SEM) to determine size and morphology and laser diffractionparticle analyzer to determine particle size distribution.

The particles produced from processed polyester had a mean particlediameter of 8 micrometers (μm) when compared to about 13 μm for thestarting material. It is shown, that a single stage milling according tothe present invention generated particles that were significantlysmaller than those produced by conventional cryogenic milling of therough material. The SEM photographs showed an extended porous networkproduced by the CO₂ fluid escape, which facilitated smaller particlesizes and a more uniform particle size distribution of the processedmaterial.

Additional advantages and modifications will readily occur to thoseskilled in the art. Therefore, the invention in its broader aspects isnot limited to the specific details and illustrative examples shown anddescribed herein. Accordingly, various modifications may be made withoutdeparting from the spirit or scope of the general inventive concept asdefined by the appended claims and their equivalents.

1. A method of producing particles comprising the steps of: providing aload stock comprising: an excipient that is a solid at 25° C. and 1atmosphere pressure; and optionally, a biologically active substance;contacting the load stock with a supercritical fluid to form a melt;expanding the melt across a pressure drop to form solid particlescomprising the load stock that are simultaneously dispersed, foamed andcooled to a temperature below 25° C.; and reducing the average particlesize of the solid particles using a milling device.
 2. The methodaccording to claim 1 further comprising the steps of: freezing at leasta portion of the supercritical fluid during the expanding step to formfrozen fluid particles; using the frozen fluid particles during thereducing step as a milling media for the solid particles comprising theload stock.
 3. The method according to claim 1 wherein the load stockfurther comprises a solvent.
 4. The method according to claim 3 whereinthe solvent is an organic solvent.
 5. The method according to claim 3further comprising extracting the solvent from the melt usingsupercritical fluid as an extracting agent prior to the expanding step.6. The method according to claim 1 wherein the reducing stepaccomplished by a means selected from the group consisting of milling,grinding, comminuting, micronizing, pulzerizing and jetting.
 7. Themethod according to claim 1 wherein subsequent to the reducing step thesolid particles have an average particle size of from about 0.1 to about500 micrometers (μm).
 8. The method according to claim 1 wherein theexcipient is a polymer selected from the group consisting ofpolysaccharides, polyesters, polyethers, polyanhydrides, polyglycolides,polylactic acids, polycaprolactones, polyethylene glycols andpolypeptides.
 9. The method according to claim 1 wherein thesupercritical fluid is selected from the group consisting of carbondioxide, water, nitrous oxide, dimethylether, straight chain or branchedC₁-C₆-alkanes, alkenes, alcohols, ethane, propane, fluoroform,chlorotrifluoromethane, chlorodiflueromethane, propylene, ammonia andcombinations thereof.
 10. The method according to claim 1 wherein thesupercritical fluid is carbon dioxide.
 11. A plurality of particlesproduced according to the method of claim
 1. 12. An apparatus forproducing solid particles comprising: a vessel for receiving a loadstock comprising: an excipient that is a solid at 25° C. and 1atmosphere pressure; and optionally, a biologically active substance; asupercritical fluid supply in fluid communication with the vessel;control means for selectively flowing supercritical fluid from thesupercritical fluid supply to the vessel to transform the load stock toa melt; an expansion chamber; a nozzle in fluid communication betweenthe vessel and the expansion chamber for expanding the expanding acrossa pressure drop to form solid particles comprising the load stock thatare cooled to a temperature below 25° C.; and a milling device in fluidcommunication with the expansion chamber for reducing the averageparticle size of the solid particles before the temperature of the solidparticles is permitted to rise to or above 25° C.
 13. A method ofproducing particles comprising the steps of: providing a load stockcomprising: an excipient that is a solid at 25° C. and 1 atmospherepressure; and optionally, a biologically active substance; contactingthe load stock with a supercritical fluid in a pressure vessel to form amelt; releasing the pressure within the pressure vessel to transform themelt into a solid porous mass that is cooled to a temperature below 25°C.; and milling the solid porous mass to obtain solid particles.
 14. Themethod according to claim 13 wherein the solid porous mass is milledbefore the temperature of the solid porous mass is permitted to rise toor above 25° C.
 15. The method according to claim 13 wherein subsequentto the reducing step the solid particles have an average particle sizeof from about 0.1 to about 500 micrometers (μm).
 16. The methodaccording to claim 13 wherein the excipient is a polymer selected fromthe group consisting of polysaccharides, polyesters, polyethers,polyanhydrides, polyglycolides, polylactic acids, polycaprolactones,polyethylene glycols and polypeptides.
 17. The method according to claim13 wherein the supercritical fluid is selected from the group consistingof carbon dioxide, water, nitrous oxide, dimethylether, straight chainor branched C₁-C₆-alkanes, alkenes, alcohols, ethane, propane,fluoroform, chlorotrifluoromethane, chlorodiflueromethane, propylene,ammonia and combinations thereof.
 18. The method according to claim 13wherein the supercritical fluid is carbon dioxide.
 19. A plurality ofparticles produced according to the method of claim 13.